Synthesis of substituted benzamides as anti-inflammatory agents that inhibit preferentially cyclooxygenase 1 but do not cause gastric damage

Parsalmide (5-amino-N-butyl-2-(2-propynyloxy) benzamide) (5a), is a non-ste roidal anti-inflammatory drug (NSAID), commercialised in Italy until 1985 w ith the brand name of Synovial(R), that has been widely used to treat arthr itic patient. In addition, it was shown to spare gastric mucosa. Here we ha ve synthesised a series of novel substituted benzamides, related to Parsalm ide, and have evaluated their activity in vitro on COX-1 and COX-2 as well as in vivo in the carrageenin-induced rat paw edema, a classical in vivo an ti-inflammatory assay. Compounds 5b, 11a and 11b, which showed a favourable profile in vitro and in vivo, were screened in comparison with Parsalmide for gastrointestinal (GI) tolerability in vivo in the rat. Results obtained showed that Parsalmide and compound 11b inhibited both COX-1 and COX-2 in vitro as well as they were active in vivo. Both compounds were devoid of ga stric effect at the efficacious dose. In addition, both prevented indometha cin-induced gastric damage. Thus, these compounds may guide the definition of a new leading structure with anti-inflammatory activity that may allow d esigning new safer NSAIDs. (C) 2001 Editions scientifiques et medicales Els evier SAS.